tbuckley/cabot-search huggingface dataset:
Factor H–Related Protein 1 Drives Disease Susceptibility and Prognosis in C3 Glomerulopathy
Authors: Bárbara Márquez-Tirado, Josué Gutiérrez-Tenorio, Agustín Tortajada, Laura Lucientes Continente, Fernando Caravaca-Fontán, Talat H. Malik, Raquel Roldán Montero, Sandra Elías, Ana Saiz Gonzalez, Gema Fernández-Juarez, Pilar Sánchez-Corral, Matthew C. Pickering, Manuel Praga, Santiago Rodríguez de Córdoba, Elena Goicoechea de Jorge
Journal: Journal of the American Society of Nephrology (2022)

Significance Statement Mutations in factor H–related protein 1 (FHR-1) that result in duplication of its dimerization domain associate with the chronic renal disease C3 glomerulopathy (C3G), which is characterized by complement dysregulation. The molecular basis for this association is only partially understood. The authors show that these FHR-1 mutations enhance FHR-1’s binding to C3-activated fragments on opsonized surfaces and promote an excessive complement activation that overcomes FH regulation. They also show that elevated levels of FHR-1 associate with poor renal prognosis for patients with C3G, whereas a genetic deficiency of FHR-1 offers protection against C3G development. These findings advance our understanding of C3G pathogenesis and suggest that inhibition of FHR-1 may have therapeutic potential in C3G. Background C3 glomerulopathy (C3G) is a heterogeneous group of chronic renal diseases characterized predominantly by glomerular C3 deposition and complement dysregulation. Mutations in factor H–related (FHR) proteins resulting in duplicated dimerization domains are prototypical of C3G, although the underlying pathogenic mechanism is unclear. Methods Using in vitro and in vivo assays, we performed extensive characterization of an FHR-1 mutant with a duplicated dimerization domain. To assess the FHR-1 mutant’s association with disease susceptibility and renal prognosis, we also analyzed CFHR1 copy number variations and FHR-1 plasma levels in two Spanish C3G cohorts and in a control population. Results Duplication of the dimerization domain conferred FHR-1 with an increased capacity to interact with C3-opsonized surfaces, which resulted in an excessive activation of the alternative pathway. This activation does not involve C3b binding competition with factor H. These findings support a scenario in which mutant FHR-1 binds to C3-activated fragments and recruits native C3 and C3b; this leads to formation of alternative pathway C3 convertases, which increases deposition of C3b molecules, overcoming FH regulation. This suggests that a balanced FHR-1/FH ratio is crucial to control complement amplification on opsonized surfaces. Consistent with this conceptual framework, we show that the genetic deficiency of FHR-1 or decreased FHR-1 in plasma confers protection against developing C3G and associates with better renal outcome. Conclusions Our findings explain how FHR-1 mutants with duplicated dimerization domains result in predisposition to C3G. They also provide a pathogenic mechanism that may be shared by other diseases, such as IgA nephropathy or age-related macular degeneration, and identify FHR-1 as a potential novel therapeutic target in C3G.
Development of nanoscale drug delivery systems of dihydroartemisinin for cancer therapy: A review
Authors: Ka Hong Wong, Donglin Yang, Shanshan Chen, Chengwei He, Meiwan Chen
Journal: Asian Journal of Pharmaceutical Sciences (2022)

Dihydroartemisinin (DHA), a first-line antimalarial drug, has demonstrated great anticancer effects in many types of tumors, including liver cancer, glioblastoma, and pancreatic cancer. Due to its abilities to induce programmed cell death (PCD; apoptosis, autophagy and ferroptosis), inhibit tumor metastasis and angiogenesis, and modulate the tumor microenvironment, DHA could become an antineoplastic agent in the foreseeable future. However, the therapeutic efficacy of DHA is compromised owing to its inherent disadvantages, including poor stability, low aqueous solubility, and short plasma half-life. To overcome these drawbacks, nanoscale drug delivery systems (NDDSs), such as polymeric nanoparticles (NPs), liposomes, and metal-organic frameworks (MOFs), have been introduced to maximize the therapeutic efficacy of DHA in either single-drug or multidrug therapy. Based on the beneficial properties of NDDSs, including enhanced stability and solubility of the drug, prolonged circulation time and selective accumulation in tumors, the outcomes of DHA-loaded NDDSs for cancer therapy are significantly improved compared to those of free DHA. This review first summarizes the current understanding of the anticancer mechanisms of DHA and then provides an overview of DHA-including nanomedicines, aiming to provide inspiration for further application of DHA as an anticancer drug.
Changing causes of death in persons with haematological cancers 1975–2016
Authors: Lezong Chen, Yongqiang Zheng, Kai Yu, Shuzhao Chen, Weida Wang, Robert Peter Gale, Ze-Xian Liu, Yang Liang
Journal: Leukemia (2022)

Abstract Causes of death in persons with haematological cancers include the index cancer, a new cancer or a seemingly unrelated cause such as cardio-vascular disease. These causes are complex and sometimes confounded. We analyzed trends in cause of death in 683,333 persons with an index haematological cancer diagnosed in 1975–2016 reported in the Surveillance, Epidemiology and End Results dataset. Non-cancer deaths were described using standardized mortality ratios. The index cancer was the predominant cause of death amongst persons with plasma cell myeloma, acute lymphoblastic leukaemia and acute myeloid leukaemia. Non-cancer death was the major cause of death in persons with chronic lymphocytic leukaemia, Hodgkin lymphoma and chronic myeloid leukaemia, mostly from cardio-vascular diseases. The greatest relative decrease in index-cancer deaths was amongst persons with Hodgkin lymphoma, chronic myeloid leukaemia and chronic lymphocytic leukaemia, where the proportion of non-cancer deaths increased substantially. Changing distribution of causes of death across haematological cancers reflects substantial progress in some cancers and suggests strategies to improve the survival of persons with haematological cancers in the future.
Drug development challenges in nontuberculous mycobacterial lung disease: TB to the rescue
Authors: Véronique Dartois, Thomas Dick
Journal: The Journal of Experimental Medicine (2022)

Nontuberculous mycobacterial pulmonary disease (NTM-PD) is treated with multiple repurposed drugs. Chemotherapy is long and often toxic, includes parenteral drugs, and suffers from poor cure rates. There is an urgent need for more efficacious, tolerated, and oral antibiotics optimized towards the treatment of NTM-PD, adapted to the spectrum of disease. In contrast to the empty NTM pipeline, drug development for the related tuberculosis lung disease has experienced a renaissance. Here, we argue that applying lessons learned from tuberculosis will facilitate the discovery of curative oral regimens for NTM-PD.
Pembrolizumab in Combination with Neoadjuvant Chemoradiotherapy for Patients with Resectable Adenocarcinoma of the Gastroesophageal Junction
Authors: Mojun Zhu, Chunhua Chen, Nathan R. Foster, Christopher Hartley, Taofic Mounajjed, Marcela A. Salomao, Briant F. Fruth, Staci E. Beamer, Yohan Kim, Susan M. Harrington, Henry C. Pitot, Cristobal T. Sanhueza, Yening Feng, Joerg Herrmann, Robert R. McWilliams, Fabrice Lucien, Bing Q. Huang, Wen Wee Ma, Tanios S. Bekaii-Saab, Haidong Dong, Dennis Wigle, Daniel H. Ahn, Chris L. Hallemeier, Shanda Blackmon, Harry H. Yoon
Journal: Clinical Cancer Research (2022)

Abstract Purpose: This phase Ib/2 trial investigated pembrolizumab-containing trimodality therapy in patients with gastroesophageal junction (GEJ) adenocarcinoma. Patients and Methods: Patients with GEJ adenocarcinoma (cT1–3NanyM0) received neoadjuvant pembrolizumab-containing chemoradiation (CROSS regimen) followed by surgical resection and adjuvant pembrolizumab. The primary endpoints were tolerability in the first 16 patients and pathologic complete response [pCR (ypT0N0)]. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). An independent propensity-score-matched cohort (treated with CROSS without immunotherapy) was used for comparison. Exploratory analyses included immune biomarkers in the tumor microenvironment (TME) and plasma. Results: We enrolled 31 eligible patients, of whom 29 received all expected doses of neoadjuvant pembrolizumab and 28 underwent R0 resection. Safety endpoints were met. The primary efficacy endpoint was not met [7/31 (22.6%) achieved pCR]. Patients with high [i.e., combined positive score (CPS) ≥ 10] baseline expression of programmed death (PD)-L1 in the TME had a significantly higher pCR rate than those with low expression [50.0% (4/8) vs. 13.6% (3/22); P = 0.046]. Patients with high PD-L1 expression also experienced longer PFS and OS than propensity-score-matched patients. Among trial patients with PD-L1 CPS &amp;lt; 10, unprespecified analysis explored whether extracellular vesicles (EV) could identify further responders: an elevated plasma level of PD-L1–expressing EVs was significantly associated with higher pCR. Conclusions: Adding pembrolizumab to trimodality therapy showed acceptable tolerability but did not meet the pre-specified pCR endpoint. Exploratory analyses suggested that high PD-L1 expression in the TME and/or on EVs may identify patients most likely to achieve tumor response.
Genetic Testing for Early-Onset Atrial Fibrillation—Is It Time to Personalize Care?
Authors: Elizabeth M. McNally, Sadiya S. Khan
Journal: JAMA Cardiology (2022)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Cardiology HomeNew OnlineCurrent IssueFor Authors Podcast Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Cardiology journal
What have we learned from genome-wide association studies (GWAS) in Parkinson's disease?
Authors: Rubén Fernández-Santiago, Manu Sharma
Journal: Ageing Research Reviews (2022)

After fifteen years of genome-wide association studies (GWAS) in Parkinson's disease (PD), what have we learned? Addressing this question will help catalogue the progress made towards elucidating disease mechanisms, improving the clinical utility of the identified loci, and envisioning how we can harness the strides to develop translational GWAS strategies. Here we review the advances of PD GWAS made to date while critically addressing the challenges and opportunities for next-generation GWAS. Thus, deciphering the missing heritability in underrepresented populations is currently at the reach of hand for a truly comprehensive understanding of the genetics of PD across the different ethnicities. Moreover, state-of-the-art GWAS designs hold a true potential for enhancing the clinical applicability of genetic findings, for instance, by improving disease prediction (PD risk and progression). Lastly, advanced PD GWAS findings, alone or in combination with clinical and environmental parameters, are expected to have the capacity for defining patient enriched cohorts stratified by genetic risk profiles and readily available for neuroprotective clinical trials. Overall, envisioning future strategies for advanced GWAS is currently timely and can be instrumental in providing novel genetic readouts essential for a true clinical translatability of PD genetic findings.
Trajectory of long covid symptoms after covid-19 vaccination: community based cohort study
Authors: Daniel Ayoubkhani, Charlotte Bermingham, Koen B Pouwels, Myer Glickman, Vahé Nafilyan, Francesco Zaccardi, Kamlesh Khunti, Nisreen A Alwan, A Sarah Walker
Journal: BMJ (2022)

Abstract Objective To estimate associations between covid-19 vaccination and long covid symptoms in adults with SARS-CoV-2 infection before vaccination. Design Observational cohort study. Setting Community dwelling population, UK. Participants 28 356 participants in the Office for National Statistics COVID-19 Infection Survey aged 18-69 years who received at least one dose of an adenovirus vector or mRNA covid-19 vaccine after testing positive for SARS-CoV-2 infection. Main outcome measure Presence of long covid symptoms at least 12 weeks after infection over the follow-up period 3 February to 5 September 2021. Results Mean age of participants was 46 years, 55.6% (n=15 760) were women, and 88.7% (n=25 141) were of white ethnicity. Median follow-up was 141 days from first vaccination (among all participants) and 67 days from second vaccination (83.8% of participants). 6729 participants (23.7%) reported long covid symptoms of any severity at least once during follow-up. A first vaccine dose was associated with an initial 12.8% decrease (95% confidence interval −18.6% to −6.6%, P&lt;0.001) in the odds of long covid, with subsequent data compatible with both increases and decreases in the trajectory (0.3% per week, 95% confidence interval −0.6% to 1.2% per week, P=0.51). A second dose was associated with an initial 8.8% decrease (95% confidence interval −14.1% to −3.1%, P=0.003) in the odds of long covid, with a subsequent decrease by 0.8% per week (−1.2% to −0.4% per week, P&lt;0.001). Heterogeneity was not found in associations between vaccination and long covid by sociodemographic characteristics, health status, hospital admission with acute covid-19, vaccine type (adenovirus vector or mRNA), or duration from SARS-CoV-2 infection to vaccination. Conclusions The likelihood of long covid symptoms was observed to decrease after covid-19 vaccination and evidence suggested sustained improvement after a second dose, at least over the median follow-up of 67 days. Vaccination may contribute to a reduction in the population health burden of long covid, although longer follow-up is needed.
Trends in the epidemiology of catheter-related bloodstream infections; towards a paradigm shift, Spain, 2007 to 2019
Authors: Laia Badia-Cebada, Judit Peñafiel, Patrick Saliba, Marta Andrés, Jordi Càmara, Dolors Domenech, Emili Jiménez-Martínez, Anna Marrón, Encarna Moreno, Virginia Pomar, Montserrat Vaqué, Enric Limón, Úrsula Masats, Miquel Pujol, Oriol Gasch
Journal: Eurosurveillance (2022)

BackgroundCatheter-related bloodstream infections (CRBSI) are frequent healthcare-associated infections and an important cause of death.AimTo analyse changes in CRBSI epidemiology observed by the Infection Control Catalan Programme (VINCat).MethodsA cohort study including all hospital-acquired CRBSI episodes diagnosed at 55 hospitals (2007-2019) in Catalonia, Spain, was prospectively conducted. CRBSI incidence rates were adjusted per 1,000 patient days. To assess the CRBSI rate trend per year, negative binomial models were used, with the number of events as the dependent variable, and the year as the main independent variable. From each model, the annual rate of CRBSI diagnosed per 1,000 patient days and the incidence rate ratio (IRR) with its 95% confidence intervals (CI) were reported.ResultsDuring the study, 9,290 CRBSI episodes were diagnosed (mean annual incidence rate: 0.20 episodes/1,000 patient days). Patients' median age was 64.1 years; 36.6% (3,403/9,290) were female. In total, 73.7% (n = 6,845) of CRBSI occurred in non-intensive care unit (ICU) wards, 62.7% (n = 5,822) were related to central venous catheter (CVC), 24.1% (n = 2,236) to peripheral venous catheters (PVC) and 13.3% (n = 1,232) to peripherally-inserted central venous catheters (PICVC). Incidence rate fell over the study period (IRR: 0.94; 95%CI: 0.93-0.96), especially in the ICU (IRR: 0.88; 95%CI: 0.87-0.89). As a whole, while episodes of CVC CRBSI fell significantly (IRR: 0.88; 95%CI: 0.87-0.91), peripherally-inserted catheter CRBSI (PVC and PICVC) rose, especially in medical wards (IRR PICVC: 1.08; 95%CI: 1.05-1.11; IRR PVC: 1.03; 95% 1.00-1.05).ConclusionsOver the study, CRBSIs associated with CVC and diagnosed in ICUs decreased while episodes in conventional wards involving peripherally-inserted catheters increased. Hospitals should implement preventive measures in conventional wards.
Awareness, loneliness, and demand for mental health services in the NHS
Authors: Yasmin Al-Haboubi, Kenny Oladimeji
Journal: BMJ (2022)

This week marks the 22nd annual mental health awareness week.Raising awareness helps to reduce the stigma of mental ill health and can help more people come forward to seek the support they need.It also helps to highlight the scale of mental ill health and unmet need, and strengthen the case for continued support and investment to improve and expand mental health services.Raising awareness feels more important than ever this year amid widespread concern about a host of issues both at home and abroad and the impact of these on people's mental health, as well as their impact on the level of focus and priority we give to mental health at a national level.
Antibody responses against SARS-CoV-2 variants induced by four different SARS-CoV-2 vaccines in health care workers in the Netherlands: A prospective cohort study
Authors: Marit J. van Gils, Ayesha Lavell, Karlijn van der Straten, Brent Appelman, Ilja Bontjer, Meliawati Poniman, Judith A. Burger, Melissa Oomen, Joey H. Bouhuijs, Lonneke A. van Vught, Marleen A. Slim, Michiel Schinkel, Elke Wynberg, Hugo D. G. van Willigen, Marloes Grobben, Khadija Tejjani, Jacqueline van Rijswijk, Jonne L. Snitselaar, Tom G. Caniels, Alexander P. J. Vlaar, Maria Prins, Menno D. de Jong, Godelieve J. de Bree, Jonne J. Sikkens, Marije K. Bomers, Rogier W. Sanders
Journal: PLoS Medicine (2022)

Emerging and future SARS-CoV-2 variants may jeopardize the effectiveness of vaccination campaigns. Therefore, it is important to know how the different vaccines perform against diverse SARS-CoV-2 variants.
High-flow nasal oxygen versus conventional oxygen therapy in patients with COVID-19 pneumonia and mild hypoxaemia: a randomised controlled trial
Authors: Claudia Crimi, Alberto Noto, Fabiana Madotto, Mariachiara Ippolito, Santi Nolasco, Raffaele Campisi, Stefano De Vuono, Giuseppe Fiorentino, Ioannis Pantazopoulos, Athanasios Chalkias, Alessandro Libra, Alessio Mattei, Raffaele Scala, Enrico M Clini, Begum Ergan, Manel Lujan, Joao Carlos Winck, Antonino Giarratano, Annalisa Carlucci, Cesare Gregoretti, Paolo Groff, Andrea Cortegiani
Journal: Thorax (2022)

Rationale In patients with COVID-19 pneumonia and mild hypoxaemia, the clinical benefit of high-flow nasal oxygen (HFNO) remains unclear. We aimed to examine whether HFNO compared with conventional oxygen therapy (COT) could prevent escalation of respiratory support in this patient population. Methods In this multicentre, randomised, parallel-group, open-label trial, patients with COVID-19 pneumonia and peripheral oxygen saturation (SpO 2 ) ≤92% who required oxygen therapy were randomised to HFNO or COT. The primary outcome was the rate of escalation of respiratory support (ie, continuous positive airway pressure, non-invasive ventilation or invasive mechanical ventilation) within 28 days. Among secondary outcomes, clinical recovery was defined as the improvement in oxygenation (SpO 2 ≥96% with fractional inspired oxygen (FiO 2 ) ≤30% or partial pressure of arterial carbon dioxide/FiO 2 ratio &gt;300 mm Hg). Results Among 364 randomised patients, 55 (30.3%) of 181 patients assigned to HFNO and 70 (38.6%) of 181 patients assigned to COT underwent escalation of respiratory support, with no significant difference between groups (absolute risk difference −8.2% (95% CI −18% to +1.4%); RR 0.79 (95% CI 0.59 to 1.05); p=0.09). There was no significant difference in clinical recovery (69.1% vs 60.8%; absolute risk difference 8.2% (95% CI −1.5% to +18.0%), RR 1.14 (95% CI 0.98 to 1.32)), intensive care unit admission (7.7% vs 11.0%, absolute risk difference −3.3% (95% CI −9.3% to +2.6%)), and in hospital length of stay (11 (IQR 8–17) vs 11 (IQR 7–20) days, absolute risk difference −1.0% (95% CI −3.1% to +1.1%)). Conclusions Among patients with COVID-19 pneumonia and mild hypoxaemia, the use of HFNO did not significantly reduce the likelihood of escalation of respiratory support. Trial registration number NCT04655638 .
Abstract A039: Transcriptomic analysis of canine osteosarcoma from a precision medicine perspective reveals limitations of differential gene expression studies
Authors: Rebecca L. Nance, Sara Cooper, Dmytro Starenki, Xu Wang, Maninder Sandey, Jey Koehler, Payal Agarwal, Brad Matz, Stephanie Lindley, Annette Smith, Ashley Smith, Noelle Bergman, Bruce F. Smith
Journal: Cancer Research (2022)

Abstract Despite significant advances in cancer diagnosis and treatment, osteosarcoma (OSA), an aggressive primary bone tumor, has eluded attempts at improving patient survival for many decades. Spontaneously occurring OSA in the dog shares remarkably similar clinical, histological, and molecular characteristics and therefore serves as an excellent model for the disease. The difficulty in managing OSA lies in its extreme genetic complexity, drug-resistance, and heterogeneity, making it improbable that a single-target treatment would be beneficial for the majority of affected individuals. Precision medicine seeks to fill this gap by addressing the intra- and inter-tumoral heterogeneity to improve patient outcome and survival. Characterization of differentially expressed genes (DEGs) provides insight into the phenotype and can be useful for informing appropriate therapies as well as development of novel treatments. To identify relevant DEGs, RNA profiles of primary tumor should be contrasted with that of normal tissue derived from the same cell-of-origin as the tumor prior to chemotherapy, as convoluted drug-resistant pathways make interpretation difficult. Traditional DEG analysis combines patient data to derive statistically inferred genes that are dysregulated in the group; however, the results from this approach are not necessarily consistent across individual patients, thus contradicting the basis of precision medicine. In this preliminary study, we use transcriptomic sequencing of RNA isolated from primary canine OSA tumor and patient-matched normal bone from seven dogs prior to chemotherapy to identify DEGs in the group. We then evaluate the universality of these changes in transcript levels among patients by deriving individual-level fold-change values using strict filtering parameters. The results from this study can be useful for reframing our perspective of transcriptomic analysis from a precision medicine perspective by identifying variations in DEGs among individuals. Citation Format: Rebecca L. Nance, Sara Cooper, Dmytro Starenki, Xu Wang, Maninder Sandey, Jey Koehler, Payal Agarwal, Brad Matz, Stephanie Lindley, Annette Smith, Ashley Smith, Noelle Bergman, Bruce F. Smith. Transcriptomic analysis of canine osteosarcoma from a precision medicine perspective reveals limitations of differential gene expression studies [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr A039.